CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

Yuri A Zarate¹, Tomoko Uehara², Kota Abe³, Masayuki Oginuma³, Sora Harako⁴, Shizuka Ishitani³, Anna-Elina Lehesjoki⁵, Tatjana Bierhals⁶, Katja Kloth⁶, Nadja Ehmke⁷, Denise Horn⁷, Manuel Holtgrewe^{8

9}, Katherine Anderson¹⁰, David Viskochil¹¹, Courtney L Edgar-Zarate¹², Maria J Guillen Sacoto¹³, Rhonda E Schnur¹³, Michelle M Morrow¹³, Amarilis Sanchez-Valle¹⁴, John Pappas¹⁵, Rachel Rabin¹⁵, Mikko Muona^{5

16}, Anna-Kaisa Anttonen^{5

17}, Konrad Platzer¹⁸, Johannes Luppe¹⁸, Janina Gburek-Augustat¹⁹, Tadashi Kaname²⁰, Nobuhiko Okamoto²¹, Seiji Mizuno²², Yusaku Kaido⁴, Yoshiaki Ohkuma⁴, Yutaka Hirose⁴, Tohru Ishitani³, Kenjiro Kosaki²

Affiliations

¹ Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA. yazarate@uams.edu.
² Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
³ Department of Homeostatic Regulation, Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
⁴ Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
⁵ Folkhälsan Research Center and University of Helsinki, Helsinki, Finland.
⁶ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁷ Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁸ Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁹ Core Unit Bioinformatics - CUBI, Berlin Institute of Health, Berlin, Germany.
¹⁰ Department of Pediatrics, University of Vermont Medical Center, Burlington, VT, USA.
¹¹ Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
¹² Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
¹³ GeneDx, Gaithersburg, MD, USA.
¹⁴ Division of Genetics and Metabolism, Department of Pediatrics, University of South Florida, Tampa, FL, USA.
¹⁵ NYU Grossman School of Medicine, Dept of Pediatrics, Clinical Genetic Services, New York, NY, USA.
¹⁶ Blueprint Genetics, Helsinki, Finland.
¹⁷ Department of Genetics, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.
¹⁸ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
¹⁹ Division of Neuropaediatrics, Hospital for Children and Adolescents, University Leipzig, Leipzig, Germany.
²⁰ Department of Genome Medicine, National Center for Child Health and Developemt, Tokyo, Japan.
²¹ Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka, Japan.
²² Department of Clinical Genetics, Central Hospital, Aichi Developmental Disability Center, Aichi, Japan.

PMID: 33495529
DOI: 10.1038/s41436-020-01091-9

Free article

CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

Yuri A Zarate et al. Genet Med. 2021 Jun.

Free article

. 2021 Jun;23(6):1050-1057.

doi: 10.1038/s41436-020-01091-9. Epub 2021 Jan 25.

Authors

Affiliations

¹ Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA. yazarate@uams.edu.
² Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
³ Department of Homeostatic Regulation, Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
⁴ Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
⁵ Folkhälsan Research Center and University of Helsinki, Helsinki, Finland.
⁶ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁷ Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁸ Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁹ Core Unit Bioinformatics - CUBI, Berlin Institute of Health, Berlin, Germany.
¹⁰ Department of Pediatrics, University of Vermont Medical Center, Burlington, VT, USA.
¹¹ Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
¹² Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
¹³ GeneDx, Gaithersburg, MD, USA.
¹⁴ Division of Genetics and Metabolism, Department of Pediatrics, University of South Florida, Tampa, FL, USA.
¹⁵ NYU Grossman School of Medicine, Dept of Pediatrics, Clinical Genetic Services, New York, NY, USA.
¹⁶ Blueprint Genetics, Helsinki, Finland.
¹⁷ Department of Genetics, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.
¹⁸ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
¹⁹ Division of Neuropaediatrics, Hospital for Children and Adolescents, University Leipzig, Leipzig, Germany.
²⁰ Department of Genome Medicine, National Center for Child Health and Developemt, Tokyo, Japan.
²¹ Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka, Japan.
²² Department of Clinical Genetics, Central Hospital, Aichi Developmental Disability Center, Aichi, Japan.

PMID: 33495529
DOI: 10.1038/s41436-020-01091-9

Abstract

Purpose: To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19.

Methods: Individuals were identified through international collaboration. Functional studies included autophosphorylation assays for CDK19 Gly28Arg and Tyr32His variants and in vivo zebrafish assays of the CDK19^G28R and CDK19^Y32H.

Results: We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19, including two recurrent changes at residues Tyr32 and Gly28. In vitro autophosphorylation and substrate phosphorylation assays revealed that kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein. Injection of CDK19 messenger RNA (mRNA) with either the Tyr32His or the Gly28Arg variants using in vivo zebrafish model significantly increased fraction of embryos with morphological abnormalities. Overall, the phenotype of the now 14 individuals with CDK19-related disorder includes universal developmental delay and facial dysmorphism, hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%).

Conclusion: CDK19 de novo missense variants are responsible for a novel neurodevelopmental disorder. Both kinase assay and zebrafish experiments showed that the pathogenetic mechanism may be more diverse than previously thought.

PubMed Disclaimer

References

1. Malumbres, M. Cyclin-dependent kinases. Genome Biol. 15, 122 (2014). - DOI
1. Spaeth, J. M., Kim, N. H. & Boyer, T. G. Mediator and human disease. Semin. Cell Dev. Biol. 22, 776–787 (2011). - DOI
1. Calpena, E. et al. De novo missense substitutions in the gene encoding CDK8, a regulator of the mediator complex, cause a syndromic developmental disorder. Am. J. Hum. Genet. 104, 709–720 (2019). - DOI
1. Nizon, M. et al. Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect. Genet. Med. 21, 2713–2722 (2019). - DOI
1. Furumoto, T. et al. A kinase subunit of the human mediator complex, CDK8, positively regulates transcriptional activation. Genes Cells 12, 119–132 (2007). - DOI

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Grants and funding

UL1 TR002538/TR/NCATS NIH HHS/United States

LinkOut - more resources

Full Text Sources
- Elsevier Science
Other Literature Sources
- scite Smart Citations
Molecular Biology Databases
- GlyGen glycoinformatics resource
- The Weizmann Institute of Science GeneCards and MalaCards databases

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

Affiliations

CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases